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Background: Elevated serum hepatitis B virus (HBV) DNA increases the development of hepatocellular carcinoma (HCC). Rather than instantaneous DNA level, the duration of persistent HBV replication is more important in carcinogenesis. Nevertheless, most investigators evaluated the DNA level at study entry. We assessed the effects of persistently detectable serum HBV DNA on HCC recurrence., Patients and Methods: We included 230 consecutive patients undergoing curative resection between 2000 and 2006. Patients who had antiviral therapy (at diagnosis or during follow-up), fluctuating DNA (cut-off value: 100,000 copies/ml) or recurrence within 12 months of resection were excluded. Ultimately, 157 were enrolled: 89 (non-viraemia group) had consistently negative DNA (<100,000 copies/ml), while 68 (viraemia group) had consistently positive DNA (>100 000copies/ml). Serum DNA level, biochemical tests, alpha-foetoprotein (AFP) and liver dynamic computed tomography were obtained every 3 months after surgery., Results: There were no significant differences in age, gender, liver function, histology, AFP, tumour stages or follow-up duration between the two groups. During follow-up (median: 35 months), patients in the non-viraemia group had a lower 5-year cumulative recurrence rate (54.7%) than those in the viraemia group (72.9%; P=0.043). In multivariate analysis, sustained viraemia (P=0.041) increased recurrence independently., Conclusions: Persistent viraemia increased recurrence independently after surgery. To prevent long-term recurrences, antiviral therapy should be initiated in those with detectable serum HBV DNA.

Background: The accurate staging of hepatocellular carcinoma (HCC) is important in establishing treatment strategies and prognosis. Among tumor factors, microvascular invasion, one of TNM staging components and prognostic factors, is underestimated preoperatively, due to inaccuracy of imaging modalities. We investigated preoperative predictors of microvascular invasion., Methods: We reviewed 190 consecutive HCC patients given curative resection from 1999 to 2006. All were treatment-naive and monitored every 3 months after resection. Tumor recurrence, survivals, and clinicopathological factors associated with microvascular invasion were analyzed., Results: The 5-year disease-free survival (DFS) rate was 39.4%(median follow-up duration: 35 months). On resection pathology, 38.9% (74/190 patients) had microvascular invasion undetected preoperatively, using liver spiral computed tomography (CT) or angiography. Independent predictors of microvascular invasion were tumor size (P = 0.043), number (P = 0.011), and Edmondson grade (P = 0.001). Patients with Edmondson grade 1 and size <5 cm had no microvascular invasion, while those with grade > or =2 had higher incidences (7/18 patients, 38.8%) even in small tumor (<2 cm). When tumors recurred, presence of microvascular invasion independently increased incidences of multiple tumors, portal vein invasion, and diffuse-infiltrative patterns significantly., Conclusions: Preoperative predictors of microvascular invasion are tumor size, number, and Edmondson grade, which may be useful for making clinical decisions in both non-surgical and surgical candidates.

Background: Diagnostic laparoscopy is known to be a relatively safe invasive procedure. However, its use has decreased owing to the development of imaging techniques, and fewer gastroenterologists now practice diagnostic laparoscopy. Our aim was to examine the role of diagnostic laparoscopy in a gastroenterology unit in the era of advanced imaging techniques., Methods: We retrospectively reviewed 855 diagnostic laparoscopy cases. Its safety and efficacy were evaluated for various indications., Results: No mortality was observed, and complications were noted in ten patients (1.2%). Among the indications were evaluation of chronic liver disease (n = 673), liver tumor (n = 15), ascites of unknown origin and peritoneal disease (n = 142), and staging of intra-abdominal malignancy (n = 25). In patients with chronic liver disease, 461 were diagnosed as having chronic viral hepatitis, based on clinical data including imaging studies, but the diagnosis was changed to cirrhosis after a laparoscopic exam in 69 patients (15.0%). In patients with ascites of unknown origin and peritoneal disease, the diagnostic yield was 87.2% (123/141). In 24 (19.5%) of the 123 patients, the diagnosis changed or the less probable diagnosis was confirmed after laparoscopic examination. The confirmed diagnoses were mainly primary peritoneal disease, including peritoneal tuberculosis, in 17 patients, peritoneal metastatic carcinoma in five, and mesothelioma in two., Conclusions: Diagnostic laparoscopy in a gastroenterology unit is safe and useful, especially for confirmation of liver cirrhosis and primary peritoneal disease evaluation.

Unlabelled: Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were -4.25 and -0.48 log(10) copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log(10) reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well-maintained during the post-treatment follow-up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment., Conclusion: A 24-week clevudine therapy was well-tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e-CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission.

Objectives: Few noninvasive models of chronic hepatitis B (CHB) to predict liver cirrhosis have been studied. The aim of the current study is to investigate the diagnostic accuracy of two simple novel models of spleen-platelet ratio index (SPRI) and age-spleen-platelet ratio index (ASPRI) in patients with CHB., Patients and Methods: A total of 346 consecutive treatment-naïve patients with CHB were retrospectively studied. The aspartate to alanine aminotransferase ratio (AAR), age-platelet index (API), aspartate aminotransferase to platelet ratio index (APRI), SPRI, and ASPRI were compared with liver histology., Results: AAR, APRI, SPRI, API, and ASPRI correlated significantly to fibrosis stage (all P<0.001). The diagnostic accuracy of ASPRI was the highest among five tests for prediction of cirrhosis (area under receiver operating characteristic curve, AUROC=0.893). Using a cutoff score of ASPRI>12, the presence of cirrhosis could be correctly identified with a high accuracy (96.3% positive predictive value) in 35 (10.1%) of 346 patients. Similarly, using a cutoff of <5, the presence of cirrhosis could be totally excluded with 100% of negative predictive value in 120 (34.7%) of 346 patients., Conclusion: ASPRI was accurate in predicting cirrhosis and screening with ASPRI has the potential to reduce the number of liver biopsies in CHB patients.

Background: Hepatic arterial infusion chemotherapy (HAIC) has often been selected as a therapeutic option for patients with advanced hepatocellular carcinoma (HCC). The objective of the current study was to evaluate the efficacy and safety of repetitive HAIC with high-dose 5-fluorouracil (5-FU) and cisplatin given for 3 days in patients with advanced HCC., Methods: Between January 2001 and December 2004, a total of 41 patients with unresectable advanced HCC were enrolled. The patients underwent HAIC via the implantable port system with 5-FU (at a dose of 500 mg/m(2) on Days 1-3) and cisplatin (at a dose of 60 mg/m(2) on Day 2) every 4 weeks. Tumor response was assessed at the end of every 3 cycles., Results: The median age of the patients was 53 years and 34 patients (82.9%) had evidence of portal vein thrombosis. In total, 230 cycles of HAIC were administered to the 41 patients, with a median of 6 cycles given (range, 1-14 cycles). Nine patients (22.0%) achieved a partial response and 14 patients (34.1%) had stable disease. The median time to disease progression and overall survival were 7.0 months and 12.0 months, respectively. The overall survival was found to be significantly longer in the successful disease control group (patients with a complete response, partial response, and stable disease) than in the disease progression group (median of 14.0 months vs 6.0 months; P < .001). Adverse reactions were tolerable and successfully managed with conservative treatment., Conclusions: HAIC with high-dose 5-FU and cisplatin given for 3 days achieved effective and safe results in patients with advanced HCC. Therefore, repetitive short-course HAIC with high-dose 5-FU and cisplatin may be useful as an alternative therapeutic option for patients with advanced HCC., (Copyright (c) 2007 American Cancer Society.)

Unlabelled: Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n=182) or placebo (n=61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P<0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P<0.0001). ALT normalization in the clevudine group was well maintained during post-treatment follow-up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug., Conclusion: A 24-week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg-positive chronic hepatitis B.

Background and Aim: This study evaluated the long-term outcome and prognostic factors of chronic hepatitis B, based on histological grade and stage., Methods: A total of 188 patients with chronic hepatitis B were followed for a mean 119.8 months. Ultrasonography and clinical assessment were performed regularly. In addition, liver biopsy specimens were re-evaluated based on histological grade and stage., Results: During follow-up, cirrhosis developed in 62 patients, decompensation in 20 patients, and hepatocellular carcinoma (HCC) in 21 patients. The serum alanine aminotransferase (ALT) level at the time of liver biopsy was significantly correlated with the grades of lobular and porto-periportal activity. The development of cirrhosis correlated well with the grade of porto-periportal activity and stage of fibrosis. The probabilities of developing cirrhosis, decompensation and HCC were significantly higher in patients whose ALT levels were persistently elevated without flares or flared-up without normalization than in patients whose ALT levels flared-up then normalized or were normally sustained. By multivariate analysis, age and biochemical profile during follow-up were independent prognostic factors for chronic hepatitis B., Conclusions: The results demonstrate that histological grade and stage, and biochemical profile during follow-up in patients with chronic hepatitis B are important prognostic factors. Therefore, effective control of hepatitis activity might improve the long-term outcome of chronic hepatitis B patients.

Immunogenetic factors may play a role in determining the susceptibility of an individual to viral infection. The aim of current study was to investigate the association of clearance of hepatitis B virus (HBV) with promoter polymorphisms within the CC chemokine receptor 5 (CCR5) and its major ligand, regulated upon activation, normal T cells expressed and secreted (RANTES) genes. Five chemokine system polymorphisms (CCR5 Delta32, CCR5 promoter 59029G/A, 59353C/T, RANTES -403G/A, and -28C/G) were studied in a total of 698 subjects. The carriage of each genetic variant was compared among "spontaneously recovered" group (n = 243), "chronic carrier" group (n = 349), and "unexposed" group (n = 106). CCR5 59029G promoter variant was associated with clearance of HBV infection in an acute phase (OR = 1.71, P = 0.006, dominant model; OR = 2.17, P < 0.001, recessive model) and amelioration of hepatic inflammation (P = 0.003) with the control of HBV replication (P = 0.04) in chronic carriers. Interestingly, CCR5 59029 was linked completely to CCR5 59353, and CCR5 Delta32 homozygosity or heterozygosity was not found in any Korean patient. No association was seen with RANTES polymorphisms at position -403 and -28. The CCR5 59029G/CCR5 59353T polymorphism may play a role in the clearance of HBV infection., ((c) 2006 Wiley-Liss, Inc.)

Background/aims: Determination of the optimal radiotherapeutic parameters for radiotherapy of hepatocellular carcinoma (HCC) is still under investigation. The purpose of this study is to identify the risk factors associated with radiation-related morbidity., Methods: We evaluated one hundred fifty-eight patients, who were given radiotherapy for HCC between January 1992 and March 2000. Radiation-induced liver disease (RILD) was defined as the development of nonmalignant ascites without disease progression and an anicteric elevation of the alkaline phosphatase level by at least twofold. Gastrointestinal toxicity was assessed by using the RTOG-EORTC scale., Results: Six patients (3.8%) displayed RILD. In these patients, three patients had not responded to other previous treatments. Two patients with portal vein thrombosis or huge sized mass, above 10 cm, showed liver toxicity and two other patients presented with Child-Pugh class B liver cirrhosis. Eight patients (5%) had gastro-duodenal ulcers. In one of these 8 patients, the left lobe close to the stomach was involved and two patients had been treated for gastro-duodenal ulcer. In two more patients, the radiation field, with using anterior/posterior radiation ports, covered a significant volume of the gastrointestinal tract. One of eight patients had been irradiated with a large fraction size (250 cGy)., Conclusions: The efforts should be made to reduce the radiation-related complications for hepatocellular carcinoma by considering the volume and the function of remaining liver, the location of tumor, the tumor size and the severity of liver cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic autoimmune liver disease that predominantly affects middle-aged women. It is characterized by slowly progressive destruction of the small intrahepatic bile ducts together with portal inflammation, and this initially leads to fibrosis and later to cirrhosis. It is currently accepted that the pathogenesis of PBC is multifactorial with genetic and environmental factors interplaying to determine the disease onset and progression. In addition to antimitochondrial antibody (AMA), which is the hallmark of PBC and is detected in at least 90% of the patients, other autoantibodies (antinuclear antibody, anti-smooth muscle antibody and rheumatoid factor, etc.) may also be found in the patients. There is no correlation between the titer of AMAs and the disease severity. Most patients are diagnosed either during the asymptomatic phase of PBC or after presenting with non-specific symptoms. Pruritus and fatigue are the most common symptoms of PBC. The prognosis of PBC has improved significantly during the last few decades. Patients are now diagnosed earlier in its clinical course, they are more likely to be asymptomatic at diagnosis and they are more likely to receive medical treatment. A wide variety of drugs have been assessed for the treatment of this condition: such immunosuppressive agents as corticosteroids, cyclosporine and azathioprine have a weak effect on the disease's natural history. Ursodeoxycholic acid (UDCA) is the only currently approved medical treatment. For PBC patients with end-stage liver disease or an unacceptable quality of life, liver transplantation is the only accepted therapeutic option. Early diagnosis and treatment of PBC are important because effective treatment with UDCA has been shown to delay disease progression and improve rate survival in the early stage.

Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via the Toll-like receptor (TLR) 4 in hepatic stellate cells (HSCs). Here we investigated the mechanism of proinflammatory action by PGN and LTA in activated human HSCs. Following treatment with either TNF-alpha or IL-1beta, expression of TLR2 and CD14 was determined by real-time PCR and Western blotting. NF-kappaB activation was assessed by NF-kappaB-driven luciferase assay and electrophoretic mobility shift assay. Interleukin-8 (IL-8) from culture supernatant was measured by ELISA. Activated human HSCs express TLR2 and CD14, which are receptors for PGN and LTA signaling. TNF-alpha and IL-1beta significantly upregulated the expression of TLR2 mRNA and protein in HSCs. PGN and LTA induced NF-kappaB activation and stimulated production of IL-8 in HSCs. Pretreatment with TNF-alpha or IL-1beta augmented NF-kappaB activation and IL-8 production in response to PGN or LTA. Both PGN- and LTA-induced NF-kappaB activation and IL-8 secretion were completely inhibited by anti-TLR2 blocking antibody (T2.5). These findings suggest that TNF-alpha or IL-1beta primed HSCs enhance the production of IL-8 in response to PGN and LTA through augmentation of the TLR2 system.

Background/aims: The long-term virologic and biochemical changes in patients with HBeAg negative HBV infection, especially in Asia, remain unclear. To address this issue, we conducted a 3 year- retrospective, cohort study., Methods: A total of 157 patients with HBeAg negative HBV infection who were monitored without treatment were reviewed between January 1999 and March 2004. Those patients were followed up every 3 months with liver function tests and serologic tests. All patients were stratified into 3 groups; inactive carrier (IC), viremic carrier (VC) and chronic hepatitis (CH). Serum HBV DNA was measured by a hybridization assay (sensitivity: 1.4 x 10(5)) genomes/mL, Digene Diagnostics, Silver Spring, USA)., Results: The median age of enrolled patients was 42.7 years (M:F=2.3:1). By single time-point observations, the 3 year-cohort prevalence of HBeAg negative CH varied from 12.7 to 35.8% (median 20.7%) HBeAg negative CH was accumulated over time (P=0.002) and transition rates among three groups after 3 years of follow-up are as follows: IC to CH, 6.0%; IC to VC, 4.1%; VC to CH, 23.2%. VC seems to be a disease state in the middle of transition from IC to CH., Conclusions: We demonstrated the dynamic changing patterns of HBeAg negative CH with time, of which the change from IC or VC to CH was dominant.

Purpose: In order to determine the effect of additional radiotherapy (RT) after an incomplete transcatheter arterial chemoembolization (TACE) in an unresectable hepatocellular carcinoma (HCC), the treatment results of patients receiving TACE plus RT were analyzed and compared with those treated with TACE alone., Materials and Methods: One hundred and five patients with an unresectable HCC were treated with TACE from January 1992 to December 2002. In 73 of these patients, the TACE was incomplete. Among them, TACE was repeatedly performed in 35 patients (TACE group), and the remaining 38 patients were also treated with local RT (TACERT group). The patients were either in stage III or IVa, Eastern Cooperative Oncology Group 2 or less, and Child-Pugh class A or B. The average frequency of TACE prior to RT was 2 and the RT was started within 7-10 days after the TACE., Results: The 2-year survival rate was significantly higher in the TACERT than in the TACE group (36.8 % vs. 14.3%, P=0.001). According to the tumor size, the 2-year survival rates in the TACERT and TACE groups were 63% vs. 42% in 5-7 cm (P=0.22), 50% vs. 0% in 8-10 cm (P=0.03), and 17% vs. 0% in larger than 10 cm (P=0.0002) respectively., Conclusion: There was a significantly improved survival rate in the TACERT group of unresectable HCC patients than in the TACE group, particularly in case of tumors > or =8 cm in diameter. Therefore, RT in addition to TACE is strongly recommended for patients with an unresectable HCC.

Background/aims: Although the lung is the most common site of extrahepatic spread from hepatocellular carcinoma (HCC), the role of surgery for pulmonary metastasis remains unclear. The aim of this study was to evaluate the efficacy of pulmonary resection in patients with pulmonary metastasis from HCC., Methods: Between July 2000 and July 2004, a total of 6 patients with pulmonary metastasis from HCC underwent curative pulmonary resections. The patients were divided into two groups (Surgery group and Non-surgery group) according to the primary treatment modality of HCC. Medical records, imaging studies, and pathologic reports of the surgical specimens were reviewed., Results: Three patients in the surgery group underwent pulmonary resections for a solitary metastasis after hepatectomy for HCC, and they are all still alive. One of the 3 patients developed a tumor recurrence in the chest wall after pulmonary resection. The survival time after diagnosis of HCC were 79, 122, and 54 months, respectively. The survival time after pulmonary metastatectomy were 49, 39, and 20 months in the three patients. Another 3 patients in the non-surgery group, received a pulmonary metastatectomy; they had either a complete response HCC or partial radiologic response. These 3 patients developed recurrent disease in the liver. One of 3 patients died. The survival time after diagnosis of HCC were 153, 83, 12 months. The survival time after pulmonary metastatectomy were 51, 4, 2 months., Conclusions: The surgical resections of a solitary pulmonary metastasis from HCC in highly selected patients might be an effective treatment modalities for prolonged survival.

Purpose: Rapid and accurate diagnosis of spontaneous bacterial peritonitis (SBP) is mandatory for timely treatment in cirrhotic patients. The purpose of this study was to assess the usefulness of two different reagent strips, the UriSCAN and the Multistix10SG, for the rapid bedside diagnosis of SBP., Methods: A total of 75 paracenteses in 53 cirrhotic patients with ascites were performed. All ascitic fluid was analyzed with the two reagent strips, and compared with the manual cell count with differential and ascitic fluid culture. SBP was defined as an ascitic polymorphonuclear cell count > or =250/mm3., Results: SBP was diagnosed in 18 of the 75 samples. If we considered the positive UriSCAN result of 2 or more, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were all 100%. When we considered the positive UriSCAN result of 3, the sensitivity, specificity, PPV, and NPV were 67%, 100%, 100%, and 89%, respectively. When we considered the positive Multistix10SG result of 3, the sensitivity, specificity, PPV, and NPV were 50%, 100%, 100%, and 87%, respectively., Conclusion: Urine reagent strip might be useful for rapid and accurate diagnosis of SBP in cirrhotic patients with ascites.

Background/aims: The aim of this study is to elucidate the efficacy of repeated hepatic arterial infusion chemotherapy (HAIC) and different chemotherapeutic regimens for treating patients having advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT)., Methods: From Jan. 1999 and Dec. 2003, a total of 103 patients diagnosed as having HCC with PVTT, but without extrahepatic spreading, were enrolled in this study. They were stratified into two groups. Group I (67 patients) received intraarterial cisplatin (CDDP, 80 mg/m2 for 2 hours on Day 1), Group II (36 patients) received intraarterial CDDP (60 mg/m2 for 2 hours on Day 2) and 5-fluorouracil (5-FU, 500 mg/m2 for 5 hours on Day 1-3). They were scheduled to receive at least three consecutive courses of the HAIC at 1 month intervals., Results: Among the 66 patients who completed the protocol, one (2.5%) and seven (17.5%) patients of group I, and one (3.8%) and four (15.4%) of group II, exhibited complete and partial responses, respectively. The median survival period of all the patients was 6 months. Group II showed a tendency to improve the median survival compared to group I (8.5 vs 5.0 months, respectively, P=0.45). The most common adverse reaction was nausea (58.2%). However, an elevation of the total bilirubin level was more frequent in Group I than in Group II (61.3% vs 20.7%, respectively, P<0.05)., Conclusions: Repeated HAIC using CDDP achieved favorable results in a few patients with HCC with PVTT, and additional 5-FU may be useful.

Background and Aim: Large volume paracentesis (LVP) with plasma volume expansion has been used for tense or refractory ascites. However, still in question is whether it is safe and effective for the treatment of spontaneous bacterial peritonitis (SBP). We addressed this issue and conducted a study to assess safety and long-term outcome of LVP in cirrhotic patients with SBP., Methods: Forty-two randomly assigned cirrhotic patients with SBP were classified into two groups; Group 1 included 21 patients who were treated with LVP and intravenous albumin; and Group 2 included 21 patients who were treated with diuretics and intravenous albumin., Results: The overall cumulative survival rate was poor in patients with SBP (42.5% and 22.5% at 6 and 12 months, respectively). At 7 days after treatment, the blood tests were similar between the two groups. In the ascitic fluid, the white blood cell counts decreased significantly and the protein concentrations tended to increase in both groups. In-hospital days, resolution rate of SBP, and in-hospital mortality rate were similar between the two groups. Although complication rates tended to be slightly higher in Group 1, long-term cumulative survivals were similar between Group 1 and Group 2. LVP was effective in removing abdominal discomfort in patients with tense ascites without serious complication., Conclusions: LVP with intravenous albumin was as effective as diuretics with intravenous albumin for the treatment of SBP with similar mortality. LVP with intravenous albumin might be feasible for the treatment of tense or refractory ascites in cirrhotic patients with SBP.

Background/aims: Viral suppression of the hepatitis B virus (HBV) can be induced by lamivudine, but the relapse seen in many patients after cessation of lamivudine therapy is troublesome. We thought that the host immune response is important to prevent viral relapse. We compared the frequency of HBV-specific CD8+ T cells in the peripheral blood and their expansion capacity after exposure to viral antigen between the patients showing sustained HBeAg seroconversion after use of lamivudine and those patients without sustained response., Methods: We analyzed HBV-specific CD8+ T cells that were isolated from the blood of 14 patients with HLA-A2 who showed lamivudine induced HBeAg seroconversion (HBV DNA < 0.5 pg/mL, and the cells were negative for HBeAg) at the end of lamivudine therapy. The purified T cells were directly stained ex vivo, after they had been stimulate with synthetic peptide, using the HBV core 18-27-specific HLA tetramer (Tc 18-27) and monoclonal antibody to CD8. The HBV viral load was quantified by the Amplicor HBV Monitor assay., Results: In patients with a sustained HBeAg response (the sustained group) for a duration of 15.5 months of follow-up, the median number of Tc 18-27 cells out of the 5 X 10(4) CD8+ T cells was 49.5 (15-135). On the contrary, in patients who experienced relapse (the relapsed group) during a median of 7.5 months of follow-up, the median number of Tc 18-27 cells out of the 5 X 10(4) CD8+ T cells was 13.5 (0-95). Especially, among patients with a viral load of HBV DNA < 1 X 10(3) copies at the end of treatment, the median number of Tc 18-27 cells out of 5 X 10(4) CD8+ T cells was 87 (45-135) in sustained group compared to 12 (6-50) in the relapsed group. All patients in the sustained group demonstrated a vigorous expansion of the core 18-27-specific CD8+ T cells after stimulation with viral peptide, in contrast to only 3 out of 8 patients in the relapsed group., Conclusions: This study demonstrates that the frequency and functional responsiveness of the circulating HBV-specific CD8+ T cells may be important for obtaining a sustained HBeAg response to lamivudine.

Background/aims: Recent studies have shown that the genotype of hepatitis B virus (HBV) may correlate with the disease natural history and treatment outcome. However, several of these studies used low sensitivity assays in a small number of patients, and this has precluded an accurate evaluation of Korean HBV genotypes. We analyzed Korean HBV genotypes in a large population by employing a new technology, restriction fragment mass polymorphism (RFMP) using MALDI-TOF mass spectrometry, in a sensitive and specific manner., Methods: Between February 1995 and December 2003, a total of 475 patients with chronic HBV infection were enrolled. The assay is based on the mass measurement of oligonucleotides having genotypic variations of the S gene. Clinical features including the virologic status and disease progression were also evaluated., Results: The median age of the total patients was 35.5 years. Out of 475 patients, there were 162 (34.1%) inactive carriers, 172 (36.2%) had chronic hepatitis, 77 (16.2%) had liver cirrhosis and 64 (13.5%) had hepatocellular carcinoma (HCC). There were 454 patients (95.6%) with genotype C, 4 patients (0.8%) with genotype A, 16 patients (3.4%) with the mixed A and C genotype [7 patients (1.4%) with AA], and 1 patient (0.2%) with B genotype. Comparing genotype A and C, genotype A patients were all inactive carriers without HCC, whereas genotype C patients included those with chronic hepatitis, liver cirrhosis and HCC., Conclusions: HBV genotype C is highly prevalent in Korea. Although it is a small percentage, genotype A also exists and it seems to take a more benign clinical course than genotype C. Further studies are necessitated to assess the relationship between HBV genotypes and the various aspects of the diseases' clinical course.

Background/aims: There have been scant reports on the prognostic factors of fulminant hepatic failure for selecting the patients who need liver transplantation. We investigated the clinical features and prognostic factors throughout the clinical course of the disease in Korean patients with fulminant hepatic failure., Methods: Between 1992 and 2003, a total of 60 patients with fulminant hepatic failure were divided into the survival group and the non-survival group, and these groups were compared according to gender, age, etiology, values of the laboratory tests, grade of the encephalopathy that was obtained at the time of admission and the worst clinical status (hepatic encephalopathy)., Results: The mean age of the total patients was 40.9 years (M:F=31:29) and the survival rate was 28.3% (n=17). Drugs (n=25, 12 herbal medicines) and viral infection (n=24, 18 HBV infection) were most common causes. On univariate analysis, the WBC, AST, ALT, total bilirubin and HE IV stage at the time of admission were the significant factors for a poor prognosis. Total bilirubin, albumin and HE IV stage also remained as significant factors at the time of the worst clinical status. On multivariate analysis, total bilirubin (P=0.033) and ALT (P=0.042) at admission were the prognostic factors, and the progression to HE IV stage (P=0.019) or hypoalbuminemia (P=0.028) during hospitalization represented the significant factors for a poor prognosis., Conclusions: In contrast to Western countries, HBV infection and herbal medicines were major causes of fulminant hepatic failure in Korea. The total serum bilirubin level and progressive hyperbilirubinemia with HE (stage IV) during hospitalization seemed to be the most important prognostic factors, and liver transplantation should be considered before the patient reaches this status.

Background/aims: Nitric oxide (NO) is a molecule involved in vascular dilatation and pathogen suppression. It also has immunologic and regulatory functions. Liver cirrhosis is characterized by an increased risk for bacterial infections, including spontaneous bacterial peritonitis (SBP). The role of NO in SBP which develops in cirrhosis has not been clearly established. The aim of this study was to investigate the role of NO in the pathogenesis of SBP and its clinical usefulness for prediction of disease prognosis., Methods: This study was designed to investigate the changes of ascites NO in the course of treatment. Nitric oxide metabolite (nitrites+nitrates [NOx]) was measured by chemiluminescence in 84 ascites samples obtained from 84 cirrhotic patients. Among them, the 38 patients with SBP were treated with cefotaxime 2.0 g, q 12hr for 7 days. In 24 of SBP patients, ascites was obtained consecutively before treatment (day 0), during treatment (day 2), and after treatment (day 7)., Results: Ascites NO levels in the patients with SBP (n=38; 82.3 +/- 14.4 microM) were not different from those in patients with sterile ascites (n=46; 54.6 +/- 13.0 microM). There was no significant change of NO levels in sequential ascites samples during antibiotic treatment. Ascites NO level before treatment was significantly higher in SBP patients who responded to antibiotics (n=26; 101.86 microM/L) than that in SBP patients who did not respond to antibiotics (n=12; 40.03 microM/L, P=0.044). A significant direct correlation was found between ascites and serum NO levels before treatment (Pearson correlation, r2=0.86, P=0.001). Among the SBP patients, treatment response rate to antibiotics were significantly higher in those patients with pretreatment NO level > or = 80 microM/L in multivariate analysis., Conclusions: Ascites NO level was not different between ascites from SBP patients and ascites from cirrhotic patients with sterile ascites. There were no changes of ascites NO in SBP patients during treatment. Therefore ascites NO was not useful to predict the progress of SBP. Ascites NO levels reflect serum NO levels, and the patients with higher NO level may have better response to antibiotics.

Background and Aim: Hepatitis B virus (HBV) infection has been known to be hampered by immunity against hepatitis B surface antigen (HBsAg). However, HBV with mutations within the common antigenic epitope of HBsAg, the "a" determinant region, can escape from humoral immunity. Moreover, HBV infection by "a" determinant mutants in chronic HBV patients has been reported after renal transplantation. In the present study, the authors investigated HBV infection after renal transplantation despite passive immunization or resolved HBV infection., Methods: A total of 1682 patients who underwent a renal transplant between 1979 and 1998 at the Severance Hospital, Yonsei University College of Medicine, Korea, were enrolled. The sequence of the HBV genome was analyzed from two patients with antibody to HBsAg (anti-HBs) immunity., Results: Of 1682 patients who were HBsAg negative before transplantation, 21 patients were found to be HBsAg positive, with elevated aspartate aminotransferase and alanine aminotransferase levels after transplantation. Interestingly, six of 21 (28.6%) patients were anti-HBs positive before the transplantation. Sequence analysis of the cloned HBV from two of six patients with anti-HBs immunity showed no evidence of significant mutations within the "a" determinant region, suggesting a wild-type of HBV. Their donors were not exposed to HBV before transplantation (all HBV markers were negative). Seven deaths of 21 patients were ascribed to HBV-related complications., Conclusions: Regardless of anti-HBs immunity, HBV infection occurred in immunosuppressed patients in a high endemic area. The molecular mechanism and clinical impact of HBV infection after renal transplantation in patients with anti-HBs immunity should be further reappraised., (Copyright 2004 Blackwell Publishing Asia Pty Ltd)

Aim: To deduce strategic guidelines of gastric mucosa associated lymphoid tissue lymphoma (MALTOMA) by evaluating the long-term outcome of patients in respect to various treatment modalities., Methods: A total of 55 patients with MALTOMA from May 1992 to August 2002 were retrospectively reviewed., Results: Complete remission was obtained in 24 (82.8%) of 29 patients treated with anti Helicobacter pylori (H pylori) regimen only. The duration to reach complete remission was 12 months (85 percentile, 2-33 months). Five patients showed complete remission with radiation therapy (26-86 months). Two of them were H pylori treatment failure cases., Conclusion: H pylori eradication is an effective primary treatment option for low grade MALTOMA and radiation therapy could be considered in patients with no evidence of H pylori infection or who do not respond to H pylori eradication therapy 12 months after successful eradication.

Background/aims: The protective role of HBV-specific CD8+ cells is dependent on their ability to efficiently migrate to the infected liver, where they may exert an effector function. The migratory behavior of CD8+ cells is influenced by their expression of different chemokine receptors. This study was intended to analyse the pattern of chemokine receptor expression of HBV specific CD 8+ cells in chronic B viral infection., Methods: We analysed the CCR5 and CCR3 profile of HBV-specific CD8+ cells isolated from the blood and liver of patients with different patterns of HBV infection. Purified T cells were stained directly ex vivo, or after antigen-specific stimulation, using HBV peptide-specific HLA tetramers and monoclonal antibodies to CD8, CCR5 and CCR3, with analysis by flow cytometry., Results: In patients with chronic hepatitis B characterised by low levels of virus (serum HBV DNA <0.5 pg/mL) and minimal liver inflammation, analysis of circulating and intrahepatic CD8+ cells demonstrated that liver infiltrating Tc18-27-specific cells were preferentially CCR5+ (up to 80% of HBV-specific CD8+ cells), in contrast to cells of the same specificity within the circulating compartment (up to 35% of HBV-specific CD8+ cells). Furthermore, CCR3 was expressed by about 10% of Tc18-27+ cells infiltrating the liver, but was absent from circulating cells. Following HBV-specific stimulation in vitro the CCR5 expression of circulating Tc18-27-specific cells was up-regulated, to levels found in liver infiltrating cells, whereas CCR3 expression was unchanged., Conclusions: The chemokine receptor profile of HBV-specific CD8+ cells is influenced by the anatomical site of these cells, and the clinical pattern of disease. The ability of circulating HBV-specific CD8+ cells of patients with low replicating virus to upregulate CCR5 suggests that these cells may respond to increases in virus replication by efficiently migrating into the infected liver.

Background/aims: Protein induced by vitamin K absence or antagonist II (PIVKA-II) appears to be a useful tumor marker for the evaluation of patients with hepatocellular carcinoma (HCC). But the usefulness of PIVKA-II was not yet clear in Korea where hepatitis B-virus is endemic. We investigated the usefulness of PIVKA-II in the diagnosis and follow-up after treatment of HCC., Methods: We studied patients with HCC which was pathologically confirmed. PIVKA-II was measured by enzyme immunoassay. PIVKA- levels before and after treatment, in correlation with imaging studies, were analyzed for the comparison of treatment responses. Kappa index was obtained., Results: A total of 129 patients were included. 93 patients (72%) were HBsAg positive. 86 patients (67%) were PIVKA-II >40 mAU/mL. 52 patients (40%) were AFP >20 ng/mL and 77 patients (60%) were AFP < or = 20 ng/mL. Of 77 patients, 40 patients (52%) showed PIVKA-II >40 mAU/mL. 68 of 129 patients were evaluated treatment response. On the basis of radiologic response, CR was 33, PR 17, SD 12, and PD 6. Of the 33 radiologic CR patients, 30 patients were CR and 3 patients were PR by means of PIVKA-II response. Of the 17 radiologic PR patients, 6 patients were CR and 7 patients were PR. Therefore, tumor responses by radiologic and PIVKA-II were well correlated (Kappa index was 0.59)., Conclusions: PIVKA-II can be used as a useful tumor marker for patients with HCC, especially those with low levels of AFP, before and after treatment in Korea.

Background/aims: Hepatitis B virus(HBV) specific cytotoxic T lymphocyte (CTL) response is believed to play a major role in virus control and liver damage in chronic hepatitis B(CHB). We performed this study to evaluate whether HBV specific CTL could be visualized directly by tetrameric HLA-A2/core 18-27 complex(T c18-27) in the peripheral blood and liver of patients with CHB. On the basis of our results we clarified patients intrahepatic compartmentalization and correlation with HBV specific CTL and viral replication or liver damage., Methods: We stained peripheral blood mononuclear cells of 33 HLA-A2 + and 8 HLA-A2 patients with CHB with cytochrome conjugated anti-CD8 mAb and phycoerythrin conjugated T c18-27. Among these we analysed intrahepatic lymphocyte of 11 HLA-A2 + patients. We compared the frequency of T c18-27 specific CD8+ cells with serum HBV-DNA levels or alanine aminotransferase(ALT) levels., Results: The frequency of circulating T c18-27 specific CD8+ cell was higher(9-101 cells per 50,000 CD8+ cells) than background level in 14 among 33 patients. The frequency of intrahepatic T c18-27 specific CD8+ cells was 12-2100 cells per 50,000 CD8+ cells in 8 out of 11 patients whose liver was obtained This was 17.4-150 times higher than circulating T c18-27 specific CD8+ cells. The frequency of circulating T c18-27 specific CD8+ cells was increased in 10 out of 18 patients with serum HBV DNA level <0.5 pg/mL and ALT < 40 IU/L. It was increased in just 4 out of 15 patients with HBV DNA level > 800 pg/mL and ALT > 70 IU/L. The frequency of intrahepatic T c18-27 CTL tended to be lower in high levels of serum HBV DNA and was not correlated with liver inflammation., Conclusion: This study proves that if HBV-specific CTLs are barely detectable in the peripheral blood of CHB, much more HBV-specific CTLs are in the liver and most HBV-specific CTLs are infiltrated in the liver. Also, in the presence of an effective HBV specific CD8 response the inhibition of viral replication can be independent of liver damage.

Background/aims: Advanced hepatocellular carcinoma with portal vein thrombosis has a poor prognosis. This study was undertaken to evaluate the therapeutic effects of concurrent chemo-radiation therapy in advanced hepatocellular carcinoma with portal vein thrombosis., Methods: A total of 54 patients with advanced hepatocellular carcinoma (TNM stage IVa) were enrolled. Nineteen patients were treated with external beam radiotherapy (4,500 cGy/ 5 weeks) and intrahepatic arterial 5-FU infusion (500 mg on 1-5 day and 30-35 day, respectively) via implanted chemoport. The others were treated with intrahepatic arterial cisplatin infusion (80 mg/m(2))., Results: In patients treated with concurrent chemo-radiation therapy, response rates at 2nd and 6th months were 42.1% and 26.3%, respectively. In patients treated with intrahepatic arterial cisplatin therapy, response rates at 2nd and 6th months were 2.9% and 0%, respectively. The median survival time was 11.6 months in concurrent chemo-radiation therapy and 4.8 months in intrahepatic arterial cisplatin infusion therapy. Concurrent chemo-radiation therapy produced better response rates and longer survival time than those of intrahepatic arterial cisplatin infusion therapy (p<0.05)., Conclusions: Concurrent chemo-radiation therapy achieved favorable results in advanced hepatocellular carcinoma with portal vein thrombosis and can be considered as a treatment option for the management of advanced hepatocellular carcinoma.

Background/aims: Large volume paracentesis (LVP) associated with plasma volume expansion is known to be an effective and safe therapy for tense or refractory ascites in cirrhosis. Spontaneous bacterial peritonitis (SBP) is one of the frequent infections in patients with cirrhosis. We conducted a study to assess the efficacy and safety of large volume paracentesis in cirrhotic patients with SBP., Methods: We randomly assigned 40 patients with cirrhosis and SBP to either treatment with LVP (21 patients) or general management (19 patients). LVP was defined as drainage of ascitic fluid of more than 4 liters in a single tap or loss of shifting dullness after paracentesis. LVP was performed within 48 hours after the diagnosis of SBP in the LVP group. Cefotaxime was given daily in doses that varied according to the serum creatinine level in both groups. Albumin was given at a dose of 6-8 g per 1 liter of removed ascites in the LVP group., Results: After seven days of treatments, the blood chemistry test, and WBC (PMN) counts and protein concentration in the ascitic fluid were not different between the two groups. Among them, the WBC (PMN) counts were decreased significantly in both groups and protein concentrations tended to increase. Durations of abdominal tenderness and pain were shorter in the LVP group but the differences were statistically not significant. Admission periods, resolution rates of SBP after seven days of treatment, complication rates and in-hospital mortality rates were not different between the two groups., Conclusions: The two treatment methods demonstrated almost the same effectiveness and safety. The symptoms were improved slightly faster in the LVP group. We concluded that large volume paracentesis is not an absolute contraindication and can be a tolerable and safe therapy in some selected cirrhotic patients with tense ascites and SBP.